Amide derivatives as trpv1 antagonists

ABSTRACT

The present invention relates to compounds of formula (I), or pharmaceutically acceptable salts, prodrugs, salts of prodrugs, or combinations thereof, 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , and R 3 , are defined in the specification. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

This application claims priority to U.S. Ser. No. 60/954,945 filed Aug.9, 2007, and is incorporated herein by reference, in its entirety.

TECHNICAL FIELD

The present invention relates to(3S)-3-alkyl-3,6-dihydro-2H-pyridine-4-carboxamide enantiomers which areuseful for useful for treating pain, bladder overactivity, or urinaryincontinence. Pharmaceutical compositions comprising compounds of theinvention and methods for treating pain, bladder overactivity, orurinary incontinence are also included.

BACKGROUND

Nociceptors are primary sensory afferent (C and Aδ fibers) neurons thatare activated by a wide variety of noxious stimuli including chemical,mechanical, thermal, and proton (pH<6) modalities. The lipophillicvanilloid, capsaicin, activates primary sensory fibers via a specificcell surface capsaicin receptor, cloned as the transient receptorpotential vanilloid-1 (TRPV1). TRPV1 is also known as vanilloidreceptor-1 (VR1). The intradermal administration of capsaicin ischaracterized by an initial burning or hot sensation followed by aprolonged period of analgesia. The analgesic component of the TRPV1receptor activation is thought to be mediated by a capsaicin-induceddesensitization of the primary sensory afferent terminal. Thus, the longlasting anti-nociceptive effect of capsaicin has prompted the clinicaluse of capsaicin analogs as analgesic agents. Further, capsazepine, acapsaicin receptor antagonist can reduce inflammation-inducedhyperalgesia in animal models. TRPV1 receptors are also localized onsensory afferents, which innervate the bladder. Capsaicin orresiniferatoxin has been shown to ameliorate incontinence symptoms uponinjection into the bladder.

The TRPV1 receptor has been called a “polymodal detector” of noxiousstimuli since it can be activated in several ways. The receptor channelis activated by capsaicin and other vanilloids, and thus is classifiedas a ligand-gated ion channel. The TRPV1 receptor activation bycapsaicin can be blocked by the competitive TRPV1 receptor antagonist,capsazepine. The channel can also be activated by protons. Under mildlyacidic conditions (pH 6-7), the affinity of capsaicin for the receptoris increased, whereas at pH<6, direct activation of the channel occurs.In addition, when membrane temperature reaches 43° C., the channel isopened. Thus heat can directly gate the channel in the absence ofligand. The capsaicin analog, capsazepine, which is a competitiveantagonist of capsaicin, blocks activation of the channel in response tocapsaicin, acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodiumand calcium enter through the channel pore, resulting in cell membranedepolarization. This depolarization increases neuronal excitability,leading to action potential firing and transmission of a noxious nerveimpulse to the spinal cord. In addition, depolarization of theperipheral terminal can lead to release of inflammatory peptides suchas, but not limited to, substance P and CGRP, leading to enhancedperipheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouselacking the TRPV1 receptor. Electrophysiological studies of sensoryneurons (dorsal root ganglia) from these animals revealed a markedabsence of responses evoked by noxious stimuli including capsaicin,heat, and reduced pH. These animals did not display any overt signs ofbehavioral impairment and showed no differences in responses to acutenon-noxious thermal and mechanical stimulation relative to wild-typemice. The TRPV1 (−/−) mice also did not show reduced sensitivity tonerve injury-induced mechanical or thermal nociception. However, theTRPV1 knock-out mice were insensitive to the noxious effects ofintradermal capsaicin, exposure to intense heat (50-55° C.), and failedto develop thermal hyperalgesia following the intradermal administrationof carrageenan.

U.S. Pat. No. 7,129,235 describes compounds of formula (a) that arevanilloid receptor antagonists and are useful in treating pain

wherein A is pyridinyl, phenyl, thiazolyl, oxazolyl, imidazolyl, etc.,R₁₁₋₁₄ are hydrogen, alkoxy, alkyl, or hydroxy, R₆, R₇, and R₈ arehydrogen, alkyl, haloalkyl, and the like.

U.S. Application publication No. 2006/0128755 discloses compounds offormulae (b) and (c) that exhibit anti-inflammatory and analgesicactivities

wherein X_(a) is Cl or CF₃, and X₆ is N or CH.

In addition, a cyclo(hetero)alkenyl compound of formula (d) has beendisclosed in publication No. WO2005004866

wherein V is N or CH, R₃ is C₁₋₁₀ alkyl, halo, and the like, m is 0 or1, Ar¹ is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, orthiadiazolyl, X is O or S, Ar² is phenyl, pyridinyl, cyclohexyl,cyclohexenyl, and the like and are reported as vanilloid receptorinhibitors.

However, none of these compounds has the structural characteristics ofthe compounds of the present invention wherein the compounds of theinvention contain a chiral carbon center in the tetrahydropyridine ringand possess unexpected efficacy as TRPV1 antagonists.

SUMMARY

One aspect of the invention is directed towards compounds of formula(I), or pharmaceutical salts, prodrugs, salts of prodrugs, orcombinations thereof,

wherein

R¹ represents formula (i), (ii), (iii), or (iv)

R² represents formula (v), (vi), (vii), (viii), (ix), (x), (xi), or(xii)

R³ is C₁₋₆ alkyl;

R⁴ represents optional substituents of R¹, and is, at each occurrence,independently alkyl, alkenyl, alkynyl, —CN, halogen, —OR^(a), —NO₂,—N(R^(a))(R^(b)), —N(R^(b))C(O)R^(a), —N(R^(b))S(O)₂R^(a),—N(R^(b))C(O)OR^(a), —N(R^(b))C(O)N(R^(a))(R^(b)),—N(R^(b))S(O)₂N(R^(a))(R^(b)), —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))(R^(b)), —S(O)₂R^(a), —S(O)₂OR^(a), —S(O)₂N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—CN, haloalkyl, —(CR^(d)R^(e))_(q)—OR^(a),—(CR^(d)R^(e))_(q)—NO₂, —(CR^(d)R^(e))_(q)—N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)R^(a),—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂R^(a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)OR^(a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)N(R^(a))(R^(b))_(q)—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—C(O)R^(a), —(CR^(d)R^(e))_(q)—C(O)OR^(a),—(CR^(d)R^(e))_(q)—C(O)N(R^(a))(R^(b)), —(CR^(d)R^(e))_(q)—S(O)₂R^(a),—(CR^(d)R^(e))_(q)—S(O)₂OR^(a), or—(CR^(d)R^(e))_(q)—S(O)₂N(R^(a))(R^(b));

R⁵ and R⁶ are optional substituents of R², and each of which at eachoccurrence is independently alkyl, alkenyl, alkynyl, halogen, —CN,halogen, —OR^(a), —NO₂, —N(R^(a))(R^(b)), or haloalkyl;

R^(d) and R^(b), at each occurrence, are each independently hydrogen,alkyl, or haloalkyl;

R^(d) and R^(e), at each occurrence, are each independently hydrogen,alkyl, halogen, or haloalkyl;

X¹ is O or S;

m is 0, 1, 2, 3, 4, or 5;

n is 0, 1, 2, 3, or 4;

p is 0, 1, or 2;

q is 1, 2, 3, or 4; and

s is 0 or 1.

Another aspect of the present invention is a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable carriers,alone or in combination with acetaminophen, with one or morenonsteroidal anti-inflammatory drugs (NSAID), or a combination thereof.

Another aspect of the present invention is a method of treating acutecerebral ischemia, chronic pain, neuropathic pain, inflammatory pain,post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy,HIV-related neuropathy, nerve injury, rheumatoid arthritic pain,osteoarthritic pain, burns, back pain, visceral pain, cancer pain,dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia,neuritis, sciatica, pelvic hypersensitivity, pelvic pain, menstrualpain; bladder disease such as incontinence, micturition disorder, renalcolic and cystitis; inflammation such as burns, rheumatoid arthritis andosteoarthritis; neurodegenerative disease such as stroke, post strokepain and multiple sclerosis; pulmonary disease such as asthma, cough,chronic obstructive pulmonary disease (COPD) and broncho constriction;gastrointestinal disease such as gastroesophageal reflux disease (GERD),dysphagia, ulcer, irritable bowel syndrome (IBS), inflammatory boweldisease (IBD), colitis and Crohn's disease; ischemia such ascerebrovascular ischemia; emesis such as cancer chemotherapy-inducedcmcsis, or obesity, said method comprising the step of administering atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, to a subject in need thereof,alone or in combination with acetaminophen, one or more nonsteroidalanti-inflammatory drug (NSAID), or a combination thereof, and with orwithout one or more pharmaceutically acceptable carrier.

Further, the present invention provides the use of compounds of thepresent invention or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of the disease conditionsdescribed above, with or without one or more pharmaceutically acceptablecarrier, and alone, or in combination with acetaminophen, one or morenonsteroidal anti-inflammatory drug (NSAID), or a combination thereof.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION

Compounds of formula (I) are disclosed in this invention

wherein R¹, R², and R³ are as defined above in the Summary of theInvention and below in the Detailed Description. Compositions comprisingsuch compounds and methods for treating conditions and disorders usingsuch compounds and compositions are also disclosed.

For a variable that occurs more than one time in any substituent or inthe compound of the invention or any other formulae herein, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Combinations of substituents are permissible only ifsuch combinations result in stable compounds. Stable compounds arecompounds, which can be isolated from a reaction mixture.

a). DEFINITIONS

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond formed by the removal of two hydrogens.Representative examples of alkenyl include, but are not limited to,ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkyl” as used herein, means a saturated, straight or branchedchain hydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1-methylpropyl, 1-ethylpropyl,1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. The term“C₁₋₆ alkyl” as used herein, means an alkyl group, as defined herein,containing 1, 2, 3, 4, 5, or 6 carbon atom in the chain.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. The term “lower haloalkyl” means a C₁₋₆alkyl group, as defined herein, in which one, two, three, four, five,six, or seven hydrogen atoms are replaced by halogen. Representativeexamples of haloalkyl and lower haloalkyl include, but are not limitedto, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, trifluoromethyl,2,2,2-trifluoroethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, and 2-iodoethyl.

b) COMPOUNDS OF THE INVENTION

Compounds of the invention have the formula (I) as described above.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In compounds of formula (I), R¹ represents formula (i), (ii), (iii), or(iv)

wherein R⁴, m, and n are as defined in the Summary. In one embodiment,R¹ represents formula (i). In another embodiment, R¹ represents formula(ii), (iii), or (iv). In yet another embodiment, R¹ represents formula(iii). R⁴, for example, is C₁₋₆ alkyl (for example, tort-butyl),halogen, —(CR^(d)R^(e))_(q)—CN, lower haloalkyl, or —S(O)₂R^(a) whereinR^(a), R^(d), R^(e), and q are as disclosed in the Summary. R^(a), forexample, is haloalkyl. R^(d) and R^(e) are the same or different andare, for example, hydrogen or C₁₋₆ alkyl. A further example of R^(d) andR^(e) is methyl. q, for example, is 1 or 2. A further example of q is 1.R^(a), for example, is C₁₋₆ alkyl or lower haloalkyl. A further exampleof R^(a) is lower haloalkyl. A yet further example of R^(a) istrifluoromethyl. Compounds of the invention include those wherein R⁴ islocated at the fourth position of the ring as represented by R¹,relative to the point of connection of the ring to the N(H) moiety offormula (I).

R² represents formula (v), (vi), (vii), (viii), (ix), (x), (xi), or(xii)

wherein X¹, R⁶, m, n, p, and s are as defined in the Summary. In oneembodiment, R² represents formula (v). In another embodiment, R²represents formula (vi). In yet another embodiment, R² representsformula (vii) or (viii). In a further embodiment, R² represents formula(ix), (x), (xi), or (xii). R⁵, for example, is C₁₋₆ alkyl (such as, butnot limited to, methyl), halogen, or haloalkyl such as, but not limitedto, trifluoromethyl. m and n are the same or different and are, forexample, 1 or 2. A further example of m and n is 1. Examples of thecompounds of invention include those wherein R⁵ is located at the2-position of the ring as represented by R², relative to the point ofconnection of R² to the nitrogen atom of formula (I).

R³ is C₁₋₆ alkyl. In one embodiment, R³ is methyl.

It is appreciated that the present invention contemplates compounds offormula (I) with combinations of the above embodiments, includingparticular, more particular and preferred embodiments.

Accordingly, one aspect of the invention relates to a group of compoundsof formula (I), or pharmaceutically acceptable salts thereof, wherein R³is methyl, R¹ is formula (i), and R², R⁴, and n are as disclosed in theSummary.

Another aspect of the invention relates to a group of compounds offormula (I), or pharmaceutically acceptable salts thereof, wherein R³ ismethyl, R¹ is formula (ii), (iii), or (iv), and R², R⁴, and n are asdisclosed in the Summary.

Yet another aspect of the invention relates to a group of compounds offormula (I), or pharmaceutically acceptable salts thereof, wherein R³ ismethyl, R¹ is formula (iii), and R², R⁴, and n are as disclosed in theSummary.

For all the foregoing groups of compounds of formula (I), examples of asubgroup include those wherein R² is formula (v), and R⁵ and m are asdefined in the Summary.

Other examples of a subgroup include those wherein R² is formula (vi),and R⁵ and n are as defined in the Summary.

Yet other examples of a subgroup include those wherein R² is formula(vii) or (viii), and R⁵ and n are as defined in the Summary.

Yet other examples of a subgroup include those wherein R² is formula(ix), (x), (xi), or (xii), and X¹, R⁶, p, and s are as defined in theSummary.

For the above groups and subgroups of compounds of formula (I), examplesof R⁴ include, but are not limited to, C₁₋₆ alkyl (for example,tert-butyl), halogen, —(CR^(d)R^(e))_(q)—CN, lower haloalkyl, or—S(O)₂R^(a) wherein R^(a), R^(d), R^(e), and q are as disclosed in theSummary. R^(a), for example, is haloalkyl. R^(d) and R^(e) are the sameor different and are, for example, hydrogen or C₁₋₆ alkyl. A furtherexample of R^(d) and R^(e) is methyl. q, for example, is 1 or 2. Afurther example of q is 1. TV, for example, is C₁₋₆ alkyl or lowerhaloalkyl. A further example of R^(a) is lower haloalkyl. A yet furtherexample of R^(a) is trifluoromethyl. Examples of R⁵ include, but are notlimited to, C₁₋₆ alkyl (such as, but not limited to, methyl), halogen,or haloalkyl such as, but not limited to, trifluoromethyl. m and n arethe same or different and are, for example, 1 or 2. A further example ofm and n is 1.

A preferred embodiment of the invention relates to compounds of formula(II), or pharmaceutically acceptable salts thereof,

wherein R³, R⁴, and R⁵ have the values as disclosed in the Summary andthe Detailed Description sections.

Compounds of the present invention contain an asymmetrically substitutedcarbon atom in the tetrahydropyridine ring of formula (I) and (II)wherein the configuration of the carbon atom bearing R³ is assigned as(3S) isomer as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem. 1976 45, 13-30. It isunderstood that compounds of the invention are essentially free of thecorresponding (3R) isomer as depicted in formula (III). By “essentiallyfree” is meant greater than about 90% free of the (3R) enantiomers ofthe compounds, for example, greater than about 95% free of the (3R)enantiomers of the compounds, or greater than about 98% free of the (3R)enantiomers of the compounds.

It will be appreciated two or more asymmetric centers may be present inthe compounds of the invention, hence several diastereomers andenantiomers of the exemplified structures will often be possible, andthat pure diastereomers and enantiomers represent preferred embodiments.It is intended that pure diasteromers, pure enantiomers, and mixturesthereof, are within the scope of the invention.

The invention contemplates the various geometric isomers and mixturesthereof resulting from the disposition of substituents around acarbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkylgroup, or a heterocycle group. Substituents around a carbon-carbondouble bond or a carbon-nitrogen bond are designated as being of Z or Econfiguration and substituents around a cycloalkyl or heterocycle aredesignated as being of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

c) GENERAL SYNTHESIS

This invention is intended to encompass compounds of the invention whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds of the invention by metabolic processes include thoseoccurring in the human or animal body (in vivo) or processes occurringin vitro.

The synthesis of compounds of formula (I) wherein the groups R¹, R², andR³ have the meanings as set forth in the summary section unlessotherwise noted, is exemplified in the accompanying Schemes 1 and 2.

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: dba fordibenzylideneacetone; THF for tetrahydrofuran; Tf or triflate fortrifluoromethanesulfonate, BOC for tert-butoxycarbonyl; and HPLC forhigh performance liquid chromatography.

The compounds of formula (I) can be produced by, for example, thefollowing reaction scheme:

For example, piperidone compounds of general formula (1) wherein R^(p)is a nitrogen protecting group, can be subjected to reaction with chiraldiol, such as, (2R,4R)-pentane-2,4-diol or its enantiomer in thepresence of excess acid such as p-toluenesulfonic acid and in a solventsuch as benzene or toluene to provide a mixture of diastereomers, (2)and (3) wherein R¹⁰¹ is alkyl. The reaction is generally conducted atthe reflux temperature of the solvent employed. Examples of the nitrogenprotecting groups are known in the art. Non-limiting examples of thenitrogen protecting groups include benzyl, tert-butoxycarbonyl, andbenzyloxycarbonyl. The diasteromers can be separated by silica gelchromatography to afford diastereomerically pure ketals of formula (2)or (3). The nitrogen protecting group of (2) can be removed usingmethodologies known by one skilled in the art, for example, byhydrogenolysis in the presence of a catalyst such as palladium hydroxideor by treatment with trifluoroacetic acid, to provide the free amine offormula (4). (4) is converted to (5) by treatment with compounds offormula R²X¹⁰² wherein X¹⁰² is a leaving group such as triflate, halogenor aromatic sulfonates (for example, benzenesulfonate orp-toluenesulfonate) in the presence of a base such as potassiumcarbonate. The reaction is generally performed in a solvent such asdimethylsulfoxide, and at elevated temperature, for example, at about 70to about 150° C. Conversion of the ketals (5) to the correspondingketones (6) can be accomplished by treatment with an acid such as, butnot limited to, acetic acid in water, at ambient temperature (about 20to about 25° C.) until the reaction is complete. Treatment of theketones (6) with a triflating agent such as, but not limited to,1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide,in the presence of an amide base such as, but not limited to, lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide, provides enoltriflates of formula (7). Thereafter (7) can be transformed to compoundsof general formula (I) using, for example, carbon monoxide, and aminesof formula R¹NH₂, in the presence of a palladium catalyst (for example,palladium (II) acetate) and a ligand (for example, triphenylphosphine or2-dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl), and a base suchas triethylamine.

(R)-enantiomers of general formula (I) can be prepared from compounds offormula (3) using similar procedures as outlined above in Scheme 1.

The compounds of formula (I) can also be produced by, for example, usingthe following reaction scheme:

For example, a protected piperidone such as1,4-dioxa-8-azaspiro[4.5]decane (8) can be reacted with electrophiles ofgeneral formula (9), wherein X¹⁰³ is a leaving group such as halogen ortriflate to provide products of the general formula (10). The reactionis generally performed in the presence of a base such as potassiumcarbonate, in a solvent such as dimethylsulfoxide, and at elevatedtemperature, for example, at about 70 to about 150° C. Alternatively,such transformation can be effected by a palladium catalyst, in thepresence of a ligand, and a base, at an elevated temperature (forexample, about 80 to about 150° C.), and in a solvent such as anaromatic hydrocarbon (for example, toluene). An example of suitablepalladium catalyst is tris(dibenzylideneacetone)dipalladium(0).Non-limiting examples of suitable bases are cesium fluoride, potassiumfluoride, and sodium tert-butoxide. An example of a suitable ligand is2,2′-bis(diphenylphosphino)-1,1′binaphthyl. Conversion of the ketals(10) to the corresponding ketones (11) can be accomplished by treatmentwith an acid such as, but not limited to, hydrochloric acid at ambienttemperature (about 20 to about 25° C.) until the reaction is complete.Treatment of the ketones (11) with an alkylating agent R³X¹⁰⁴ (12)wherein X¹⁰⁴ is a leaving group such as halogen, triflate, or sulfate,in the presence of base and a solvent provides alkylated products offormula (13). Examples of suitable bases for the transformation include,but are not limited to sodium hydride and an amide base (for example,lithium diisopropylamide or lithium bis(trimethylsilyl)amide). Treatmentof the ketones (13) with a triflating agent such as, but not limited to,1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide,in the presence of an amide base such as, but not limited to, lithiumdiisopropylamide or lithium bis(trimethylsilyl)amide, provides enoltriflates of formula (14). Thereafter (14) can be transformed to methylesters of general formula (15) using, for example, carbon monoxide andmethanol, in the presence of a palladium catalyst (for example,palladium (II) acetate) and a ligand (for example, triphenylphosphine or2-dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl), and a base suchas triethylamine. The esters (15) can be transformed to compounds ofgeneral formula (16) using trimethylaluminum and amines of formula R¹NH₂in a solvent such toluene or dichloromethane. Single enantiomers (17)and (I) can be separated by chiral HPLC using a chiral column such as,but not limited to, a Chiralcel OD or Chiralcel AS column (ChiralTechnologies Inc., West Chester, Pa.) and solvent mixtures containingmethanol, hexane, and dichloromethane.

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the synthetic examples section are illustrative andare not to be read as limiting the scope of the invention as it isdefined in the appended claims. All alternatives, modifications, andequivalents of the synthetic methods and specific examples are includedwithin the scope of the claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions may be worked up in theconventional manner, e.g. by eliminating the solvent from the residueand further purified according to methodologies generally known in theart such as, but not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available ormay be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

d) EXAMPLES Example 1(3S)-3′-chloro-3-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamideExample 1A(2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

To a solution of 1-benzyl-3-methylpiperidin-4-one (Acros, 62.09 g, 305.4mmol) and (2S,4S)-pentane-2,4-diol (TCI-US, 34.06 g, 327.0 mmol) inbenzene (800 mL) was added p-toluenesulfonic acid mono hydrate (69.72 g,404.9 mmol). The flask was fitted with a Dean-Stark trap and heated toreflux. The reaction mixture was cooled after 16 hours of reflux,concentrated to a total volume of about 500 mL and transferred to anErlenmeyer flask with ethyl acetate. A sodium bicarbonate solution (500mL) added with stirring and the mixture was further neutralized withsolid Na₂CO₃ (35 g). The layers were partitioned, the organic phasewashed with sodium bicarbonate, dried (Na₂SO₄) and concentrated to yieldapproximately 95 g of crude material. The residue was purified in 15 gbatches by silica gel chromatography (Analogix SF-65-600 g; 35 micronsilica; elution with 10% ethyl acetate-hexane) at 50 mL/min to provide42.33 g of the first eluting isomer,(2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane.¹H NMR (300 MHz, DMSO-d₆) δ 7.33-7.19 (m, 5H), 4.07-3.86 (m, 2H), 3.40(ABq, 2H, J_(AB)=13.5 Hz, δν_(AB)=23.3 Hz), 2.41-2.20 (m, 4H), 1.90-1.76(m, 2H), 1.59-1.47 (m, 3H), 1.12 (d, 3H, J=6.4 Hz), 1.11 (d, 3H, J=6.4Hz), 0.90 (d, 3H, J=7.1 Hz); MS (DCI/NH₃) m/e 290 (M+H)⁺.

Example 1B(2S,4S,7S)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

The title compound was the later eluting isomer obtained from thepurification of the reaction mixture in Example 1A (40.82 g). ¹H NMR(300 MHz, DMSO-d₆) δ 7.35-7.19 (m, 5H), 4.04-3.91 (m, 2H), 3.40 (ABq,2H, J_(AB)=13.5 Hz, δν_(AB)=17.1 Hz), 2.44-2.38 (m, 2H), 2.26-2.15 (m,1H), 2.11-2.04 (m, 1H), 2.00-1.93 (m, 1H), 1.82-1.71 (m, 1H), 1.61-1.42(m, 3H), 1.13 (d, 3H, J=6.0 Hz), 1.11 (d, 3H, J=6.3 Hz), 0.87 (d, 3H,J=6.8 Hz); MS (DCI/NH₃) m/e 290 (M+H)⁺.

Example 1C (2S,4S,7R)-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

To a solution of(2S,4S,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecanefrom Example 1A (20.30 g, 70.20 mmol) in methanol (300 mL) was addedpalladium hydroxide (0.986 g, 7.02 mmol) and the mixture stirred under60 psi pressure of hydrogen. After 4 hours, the mixture was filtered andconcentrated to provide 13.71 g (98%) of the title compound as an oil.¹H NMR (300 MHz, CDCl₃) δ 4.06-3.97 (m, 2H), 2.94 (dd, 1H, J=12.7, 4.0Hz), 2.87 (dd, 2H, J=5.2, 5.2 Hz), 2.66 (dd, 1H, J=12.7, 5.6 Hz),1.92-1.85 (m, 1H), 1.82-1.73 (m, 1H), 1.63-1.53 (m, 4H), 1.20 (d, 3H,J=6.4 Hz), 1.19 (d, 3H, J=6.4 Hz), 0.96 (d, 3H, J=7.1 Hz); MS (DCI/NH₃)m/e 200 (M+H)⁺.

Example 1D(2S,4S,7R)-9-(3-chloropyridin-2-yl)-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

To a solution of the product from Example 1C (13.71 g, 68.79 mmol) indimethylsulfoxide (70 mL) was added potassium carbonate (19.02 g, 137.6mmol) and 2,3-dichloropyridine (12.22 g, 82.57 mmol). The reactionmixture was heated at 90° C. and stirred for 96 hours. The reactionmixture was poured into ethyl acetate (200 mL), washed with saturatedsodium bicarbonate, dried (Na₂SO₄) and concentrated. The residue waspurified by silica gel chromatography (elution with 25% ethylacetate-hexane) to provide 17.91 g (84%) of the title compound. ¹H NMR(300 MHz, CDCl₃) δ 8.14 (dd, 1H, J=4.7, 1.7 Hz), 7.54 (dd, 1H, J=7.8,1.7 Hz), 6.77 (dd, 1H, J=7.8, 4.8 Hz), 4.13-3.97 (m, 2H), 3.47-3.28 (m,4H), 2.17-2.00 (m, 2H), 1.85-1.77 (m, 1H), 1.69-1.54 (m, 2H), 1.21 (d,6H, J=6.4 Hz), 1.08 (d, 3H, J=7.1 Hz); MS (DCI/NH₃) m/e 311 (M+H)⁺.

Example 1E (3R)-1-(3-chloropyridin-2-yl)-3-methylpiperidin-4-one

A solution of the product from Example 1D (9.08 g, 29.2 mmol) in aceticacid (50.0 mL) and water (50 mL) was stirred at room temperature for 2hours. The reaction mixture was made basic with saturated sodiumbicarbonate, the layers partitioned and the aqueous layer back extractedwith ethyl acetate (2×100 mL). The organic phases were combined, dried(Na₂SO₄), and concentrated. The residue was purified by silica gelchromatography (elution with 25% ethyl acetate-hexane) to provide 6.00 g(91%) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ 8.19 (dd, 1H,J=4.8, 1.6 Hz), 7.63 (dd, 1H, J=7.9, 1.6 Hz), 6.88 (dd, 1H, J=7.5, 4.8Hz), 4.16-4.05 (m, 2H), 3.33-3.23 (m, 1H), 2.96 (dd, 1H, J=12.3, 10.7Hz), 2.86-2.73 (m, 2H), 2.50 (ddd, 1H, J=14.3, 3.2, 3.2 Hz), 1.09 (d,3H, J=6.8 Hz); MS (DCI/NH₃) m/e 225 (M+H)⁺.

Example 1F(R)-1-(3-chloropyridin-2-yl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate

To a solution of the product from Example 1E (6.00 g, 26.7 mmol) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(10.5 g, 29.4 mmol) in tetrahydrofuran (100 mL) at −78° C. was addedlithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 32.0 mL) andthe reaction mixture was stirred for 1 hour. The reaction mixture waswarmed to room temperature and stirred for an additional 1 hour,concentrated, and taken up in ethyl acetate (200 mL). The organic phasewas washed with saturated sodium bicarbonate, brine, dried (Na₂SO₄), andconcentrated. The residue was purified by silica gel chromatography(elution with 25% ethyl acetate-hexane) to provide 8.00 g (84%) of thetitle compound. ¹H NMR (300 MHz, CDCl₃) δ 8.16 (dd, 1H, J=4.8, 1.7 Hz),7.60 (dd, 1H, J=7.8, 1.7 Hz), 6.86 (dd, 1H, J=7.8, 4.8 Hz), 5.88-5.86(m, 1H), 4.04-4.01 (m, 2H), 3.78 (ddd, 1H, J=12.9, 4.8, 0.7 Hz), 3.17(dd, 1H, J=12.5, 6.8 Hz), 2.96-2.89 (m, 1H), 1.25 (d, 3H, J=7.1 Hz); MS(DCI/NH₃) m/e 357 (M+H)⁺.

Example 1G(3S)-3′-chloro-3-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

A solution of palladium (II) acetate (0.883 g, 3.94 mmol), the productfrom Example 1F (7.0 g, 19.68 mmol), triethylamine (5.48 mL, 39.4 mmol),2-dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl (3.10 g, 7.87mmol) and 4-(trifluoromethylsulfonyl)aniline (5.76 g, 25.6 mmol) inN,N-dimethylformamide (20 mL) was placed under 1 atmosphere of carbonmonoxide and stirred at room temperature for 2 hours. The reactionmixture was concentrated to approximately 10 mL, poured into 1.5 L ofethyl acetate, washed with saturated sodium bicarbonate, dried (Na₂SO₄),and concentrated. The residue was purified by silica gel chromatography(gradient elution from 0% to 20% ethyl acetate-[50% CH₂Cl₂-hexane] toprovide the title compound as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.20 (d, 1H, J=4.8, 1.7 Hz), 8.02 (d, 2H, J=8.8 Hz), 7.90 (d, 2H, J=9.1Hz), 7.81 (br s, 1H), 7.63 (dd, 1H, J=7.8, 1.7 Hz), 6.88 (dd, 1H, J=7.5,4.8 Hz), 6.65 (dd, 1H, J=3.1, 3.1 Hz), 4.20-3.97 (m, 2H), 3.64 (dd, 1H,J=12.9, 4.1 Hz), 3.34 (dd, 1H, J=12.9, 4.4 Hz), 3.11-3.07 (m, 1H), 1.29(d, 3H, J=6.4 Hz); MS (DCI/NH₃) m/e 460 (M+H)⁺; [α]²³ _(D)+34.0° (c 1.0,CH₃OH).

Example 2(3S)-3′-chloro-3-methyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamideExample 2A(2R,4R,7S)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

The title compound (6.27 g) was obtained as the first eluting isomerwhen prepared using similar procedure as described in Example 1A,substituting toluene for benzene and substituting(2R,4R)-pentane-2,4-diol for (2S,4S)-pentane-2,4-diol. ¹H NMR (300 MHz,DMSO-d₆) δ 7.33-7.19 (m, 5H), 4.07-3.86 (m, 2H), 3.40 (ABq, 2H,J_(AB)=13.5 Hz, δν_(AB)=23.3 Hz), 2.41-2.20 (m, 4H), 1.90-1.76 (m, 2H),1.59-1.47 (m, 3H), 1.12 (d, 3H, J=6.4 Hz), 1.11 (d, 3H, J=6.4 Hz), 0.90(d, 3H, J=7.1 Hz); MS (DCI/NH₃) m/e 290 (M+H)⁺.

Example 2B(2R,4R,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

The title compound (5.87 g) was the later eluting isomer obtained fromthe purification of the reaction mixture from Example 2A. ¹H NMR (300MHz, DMSO-d₆) δ 7.35-7.19 (m, 5H), 4.04-3.91 (m, 2H), 3.40 (ABq, 2H,J_(AB)=13.5 Hz, δν_(AB)=17.1 Hz), 2.44-2.38 (m, 2H), 2.26-2.15 (m, 1H),2.11-2.04 (m, 1H), 2.00-1.93 (m, 1H), 1.82-1.71 (m, 1H), 1.61-1.42 (m,3H), 1.13 (d, 3H, J=6.0 Hz), 1.11 (d, 3H, J=6.3 Hz), 0.87 (d, 3H, J=6.8Hz); MS (DCI/NH₃) m/e 290 (M+H)⁺.

Example 2C (2R,4R,7R)-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

To a solution of(2R,4R,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane(880 mg, 3.04 mmol) from Example 2B in methanol (25 mL) was addedpalladium hydroxide (82 mg) and the mixture stirred under 1 atmospherepressure of hydrogen. After 5 h, the mixture was filtered andconcentrated to provide 567 mg (94%) of the title compound as an oil. ¹HNMR (300 MHz, CDCl₃) δ 4.11-3.97 (m, 2H), 2.93-2.71 (m, 3H), 2.61 (dd,1H, J=12.3, 8.7 Hz), 1.97 (ddd, 1H, J=13.9, 5.6, 3.6 Hz), 1.79-1.70 (m,1H), 1.65-1.47 (m, 4H), 1.21 (d, 3H, J=6.4 Hz), 1.19 (d, 3H, J=6.4 Hz),0.95 (d, 3H, J=6.7 Hz); MS (DCI/NH₃) m/e 200 (M+H)⁺.

Example 2D(2R,4R,7R)-9-(3-chloropyridin-2-yl)-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane

To a solution of the product from Example 2C (1.00 g; 5.02 mmol) indimethylsulfoxide (20 mL) was added potassium carbonate (693 mg, 5.02mmol) and 2,3-dichloropyridine (891 mg, 6.02 mmol). The reaction mixturewas heated at 90° C. and stirred for 96 hours. The reaction mixture waspoured into ethyl acetate (200 mL), washed with saturated sodiumbicarbonate, dried (Na₂SO₄) and concentrated. The residue was purifiedby silica gel chromatography (elution with 25% ethyl acetate-hexane) toprovide 1.33 g (85%) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ8.15 (dd, 1H, J=4.8, 1.7 Hz), 7.56 (dd, 1H, J=7.8, 1.4 Hz), 6.78 (dd,1H, J=7.5, 4.8 Hz), 4.14-4.02 (m, 2H), 3.53-3.44 (m, 2H), 3.27-3.19 (m,1H), 3.11 (dd, 1H, J=12.2, 8.5 Hz), 2.18-2.00 (m, 2H), 1.83 (ddd, 1H,J=13.2, 9.5 Hz), 1.70-1.50 (m, 2H), 1.22 (d, 3H, J=6.4 Hz), 1.21 (d, 3H,J=6.4 Hz), 1.05 (d, 3H, J=6.8 Hz); MS (DCI/NH₃) m/e 311 (M+H)⁺.

Example 2E (3R)-1-(3-chloropyridin-2-yl)-3-methylpiperidin-4-one

A solution of the product from Example 2D (1.31 g, 4.21 mmol) in aceticacid (10.0 mL) and water (30.0 mL) was stirred at room temperature for 2hours. The reaction mixture was made basic with saturated sodiumbicarbonate, the layers partitioned and the aqueous layer back extractedwith ethyl acetate (2×100 mL). The organic phases were combined, dried(Na₂SO₄), and concentrated. The residue was purified by silica gelchromatography (elution with 25% ethyl acetate-hexane) to provide thetitle compound.

Example 2F(R)-1-(3-chloropyridin-2-yl)-3-methyl-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate

(3R)-3′-chloro-3-methyl-3,6-dihydro-2H-1,2′-bipyridin-4-yltrifluoromethanesulfonate

To a solution of the product from Example 2E (660 mg, 2.94 mmol) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(1.15 g, 3.23 mmol) in tetrahydrofuran (50.0 mL) at −78° C. was addedlithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 3.5 mL) andthe reaction mixture was stirred for 1 hour. The reaction mixture waswarmed to room temperature and stirred for an additional 1 hour,concentrated, and taken up in ethyl acetate (200 mL). The organic phasewas washed with saturated sodium bicarbonate, brine, dried (Na₂SO₄), andconcentrated. The residue was purified by silica gel chromatography(elution with 25% ethyl acetate-hexane) to provide the title compound.

Example 2G(3S)-3′-chloro-3-methyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

A solution of palladium (II) acetate (0.065 g, 0.29 mmol), the productfrom Example 2F (1.03 g, 2.90 mmol), triethylamine (0.293 mg, 2.90mmol), 2-dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl (0.228 g,0.579 mmol) and p-trifluoromethylaniline (0.933 g, 5.79 mmol) inN,N-dimethylformamide (20 mL) was placed under 1 atmosphere of carbonmonoxide and stirred at room temperature for 2 hours. The reactionmixture was concentrated to approximately, poured into of ethyl acetate,washed with saturated sodium bicarbonate, dried (Na₂SO₄), andconcentrated. The residue was purified by silica gel chromatography(gradient elution from 0% to 20% ethyl acetate-[50% CH₂Cl₂-hexane] toprovide the title compound. ¹H NMR (300 MHz, CDCl₃) δ 8.19 (dd, 1H,J=4.7, 1.7 Hz), 7.71 (d, 2H, J=8.5 Hz), 7.62 (dd, 1H, J=7.8, 1.7 Hz),7.60 (d, 2H, J=8.5 Hz), 6.86 (dd, 1H, J=7.8, 4.7 Hz), 6.61 (dd, 1H,J=3.1, 3.1 Hz), 4.19-3.96 (m, 2H), 3.63 (dd, 1H, J=12.5, 4.1 Hz), 3.35(dd, 1H, J=12.5, 4.1 Hz), 3.14-3.02 (m, 1H), 1.29 (d, 3H, J=7.1 Hz); MS(DCI/NH₃) m/e 396 (M+H)⁺; [α]²³ _(D)+37.2° (c 1.0, CH₃OH).

Example 3(3S)-3,3′-dimethyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

To a solution of the product from Example 1G (0.950 g, 2.066 mmol) indioxane (20 mL) was added 1,1′-bis(diphenylphosphino)ferrocene palladium(II) chloride (0.506 g, 0.620 mmol) followed by dimethylzinc (2 M intoluene, 2.07 mL, 4.13 mmol) and the reaction stirred at roomtemperature for 30 minutes then at 100° C. for 1 hour. The reaction wasquenched with methanol, washed with 1N HCl, dried (sodium sulfate) andconcentrated in vacuo. The residue was purified by silica gelchromatography (gradient elution 0% to 20% ethyl acetate-[50%CH₂Cl₂-hexane]) to provide 475 mg (52%) of the title compound. ¹H NMR(300 MHz, CDCl₃) δ 8.18 (dd, 1H, J=4.8, 2.0 Hz), 8.01 (d, 2H, J=8.7 Hz),7.90 (d, 2H, J=9.1 Hz), 7.83 (br s, 1H), 7.46-7.42 (m, 1H), 6.91 (dd,1H, J=7.1, 4.8 Hz), 6.68 (dd, 1H, J=3.6, 3.6 Hz), 3.95-3.93 (m, 2H),3.22 (d, 2H, J=4.0 Hz), 3.12-2.98 (m, 1H), 2.35 (s, 3H), 1.27 (d, 3H,J=7.1 Hz); MS (DCI/NH₃) m/e 440 (M+H)⁺; [α]²³ _(D)+45.0° (c 0.10,CH₃OH).

Example 4(3S)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamideExample 4A(2R,4R,7R)-2,4,7-trimethyl-9-(3-(trifluoromethyl)pyridin-2-yl)-1,5-dioxa-9-azaspiro[5.5]undecane

The title compound (1.89 g, 75%) was prepared using similar procedure asdescribed in Example 2D, substituting 2-chloro-3-trifluoromethylpyridinefor 2,3-dichloropyridine to provide of the title compound. ¹H NMR (300MHz, CDCl₃) δ 8.38 (dd, 1H, J=4.8, 1.4 Hz), 7.82 (dd, 1H, J=7.8, 1.7Hz), 6.93-6.89 (m, 1H), 4.12-4.01 (m, 2H), 3.44-3.34 (m, 2H), 3.21 (ddd,1H, J=12.5, 9.5, 3.4 Hz), 3.08 (dd, 1H, J=12.6, 8.5 Hz), 2.17-2.09 (m,1H), 2.07-2.01 (m, 1H), 1.80 (ddd, 1H, J=13.2, 9.5, 3.7 Hz), 1.70-1.50(m, 2H), 1.22 (d, 3H, J=6.1 Hz), 1.21 (d, 3H, J=6.1 Hz), 1.00 (d, 3H,J=6.8 Hz); MS (DCI/NH₃) m/e 345 (M+H)⁺.

Example 4B(3S)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound (121 mg, 10%) was prepared using similar proceduresas described in Examples 2E, 2F and 2G, substituting the product fromExample 4A for the product from Example 2D. ¹H NMR (300 MHz, CDCl₃) δ8.48 (dd, 1H, J=4.8, 1.4 Hz), 7.93 (dd, 1H, J=7.8, 2.0 Hz), 7.71 (d, 2H,J=8.5 Hz), 7.60 (d, 2H, J=8.8 Hz), 7.05 (dd, 1H, J=7.8, 4.7 Hz), 6.57(dd, 1H, J=3.4, 3.4 Hz), 4.10-3.88 (m, 2H), 3.47 (dd, 1H, J=12.2, 4.1Hz), 3.30 (dd, 1H, J=12.5, 4.4 Hz), 3.13-3.00 (m, 1H), 1.20 (d, 3H,J=6.8 Hz); MS (DCI/NH₃) m/e 430 (M+H)⁺; [α]²³ _(D)+31.6° (c 1.00,CH₃OH).

Example 5(3R)-3′-chloro-3-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound (400 mg, 52%) was prepared using similar proceduresas described in Examples 1C through 1G, substituting the product fromExample 2A for the product from Example 1A. ¹H NMR (300 MHz, CDCl₃) δ8.20 (d, 1H, J=4.8, 1.7 Hz), 8.02 (d, 2H, J=8.8 Hz), 7.90 (d, 2H, J=9.1Hz), 7.77 (br s, 1H), 7.63 (dd, 1H, J=7.8, 1.7 Hz), 6.88 (dd, 1H, J=7.5,4.8 Hz), 6.65 (dd, 1H, J=3.1, 3.1 Hz), 4.20-3.97 (m, 2H), 3.64 (dd, 1H,J=12.9, 4.1 Hz), 3.34 (dd, 1H, J=12.9, 4.4 Hz), 3.11-3.07 (m, 1H), 1.29(d, 3H, J=6.4 Hz); MS (ESI) m/e 460 (M+H)⁺; [α]²³ _(D)−30.4° (c 0.50,CH₃OH).

Example 6(3R)-3,3′-dimethyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound (51 mg, 54%) was prepared using similar procedure asdescribed in Example 3, substituting the product from Example 5 for theproduct from Example 1G. ¹H NMR (300 MHz, CDCl₃) δ 8.19-8.17 (m, 1H),8.00 (d, 2H, J=9.2 Hz), 7.90 (d, 2H, J=9.2 Hz), 7.86 (br s, 1H),7.47-7.43 (m, 1H), 6.91 (dd, 1H, J=7.1, 4.8 Hz), 6.68 (dd, 1H, J=3.4,3.4 Hz), 3.94 (app t, 2H, J=2.4 Hz), 3.23 (app d, 2H, J=4.1 Hz),3.10-2.99 (m, 1H), 2.35 (s, 3H), 1.27 (d, 3H, J=7.1 Hz); MS (DCI/NH₃)m/e 440 (M+H)⁺; [α]²³ _(D)−38.0° (c 0.25, CH₃OH).

Example 7(3R)-3′-chloro-3-methyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound (340 mg, 38%) was prepared using similar proceduresas described in Examples 2C through 2G, substituting(2R,4R,7S)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane(from Example 2A) for(2R,4R,7R)-9-benzyl-2,4,7-trimethyl-1,5-dioxa-9-azaspiro[5.5]undecane.¹H NMR (300 MHz, CDCl₃) δ 8.19 (dd, 1H, J=4.8, 1.7 Hz), 7.71 (d, 2H,J=8.5 Hz), 7.62 (dd, 1H, J=7.8, 1.7 Hz), 7.61 (d, 2H, J=8.5 Hz), 7.60(br s, 1H), 6.86 (dd, 1H, J=7.8, 4.7 Hz), 6.61 (dd, 1H, J=3.4 Hz),4.18-3.95 (m, 2H), 3.63 (dd, 1H, J=12.5, 4.1 Hz), 3.34 (dd, 1H, J=12.5,4.1 Hz), 3.15-3.02 (m, 1H), 1.29 (d, 3H, J=7.1 Hz); MS (DCI/NH₃) m/e 396(M+H)⁺; [α]²³ _(D)−28.7° (c 0.3, CH₃OH).

Example 8(3S)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound (185 mg, 24%) was prepared using similar procedure asdescribed in Example 3, substituting the product from Example 2G for theproduct from Example 1G. ¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (br s, 1H),8.13 (dd, 1H, J=4.8, 1.7 Hz), 7.93 (d, 2H, J=8.5 Hz), 7.68 (d, 2H, J=8.5Hz), 7.55-7.52 (m, 1H), 6.95 (dd, 1H, J=7.5, 5.1 Hz), 6.70 (dd, 1H,J=2.7, 2.7 Hz), 3.87-3.81 (m, 2H), 3.15-3.11 (m, 2H), 3.03-2.93 (m, 1H),2.32 (s, 3H), 1.16 (d, 3H, J=6.8 Hz); MS (DCI/NH₃) m/c 376 (M+H)¹; [α]²³_(D)+15.0° (c 0.45, CH₃OH).

Example 9(3R)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamideExample 9A 1-(3-methylpyridin-2-yl)piperidin-4-one

A mixture of 2-chloro-3-methylpyridine (5.0 mL, 45.8 mmol), Pd₂dba₃-CHCl₃ (0.958 g, 0.926 mmol), racemic2,2′-bis(diphenylphosphino)-1,1′binaphthyl (1.43 g, 2.30 mmol), sodiumtert-butoxide (8.51 g, 88.6 mmol), and 1,4-dioxa-8-azaspiro-[4.5]decane(5.6 mL, 44 mmol) in toluene (135 mL) was heated to 100° C. for 3.5hours. The mixture was then diluted with ethyl acetate, washed withwater and brine, dried over Na₂SO₄, and filtered through silica with 70%diethyl ether/hexanes to give 11.5 g of impure substituted pyridine as ared oil. This material was stirred in concentrated HCl (60 mL) for 6hours, quenched with concentrated NH₄OH (80 mL), diluted with ethylacetate, washed with water and brine, dried (Na₂SO₄), filtered throughsilica with 80% diethyl ether/hexanes, and concentrated under reducedpressure to provide the title compound, which was used without furtherpurification. MS (DCI/NH₃) m/e 191 (M+H)⁺.

Example 9B (±)-3-Methyl-1-(3-methylpyridin-2-yl)piperidin-4-one

To a suspension of sodium hydride (1.7 g, 42 mmol) in THF (80 mL) atroom temperature were added the product of Example 9A (6.65 g, 38.5mmol) and iodomethane (2.9 ml, 46 mmol) as solution in THF (8 ml) dropwise. The mixture was stirred for 5 hours at 60° C. The reaction mixturewas filtered and then concentrated under reduced pressure. The residuewas partitioned between water and ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and then concentratedunder reduced pressure. The residue was purified via silica gelchromatography (gradient elution, 0 to 30% diethyl ether-hexanes) toprovide the title compound together with a small, inseparable quantityof 3,3-dimethyl-1-(3-methylpyridin-2-yl)piperidin-4-one. MS (DCI/NH₃)m/e 205 (M+H)⁺.

Example 9C(±)-3-Methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate

The title compound was prepared using similar procedure as described inExample 1F, substituting the product from Example 9B for the productfrom Example 1E. MS (DCI/NH₃) m/e 337 (M+H)¹.

Example 9D (±)-methyl3,3′-dimethyl-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylate

To a 1:1 mixture of N,N-dimethylformamide: methanol saturated with CO,was added the product from Example 9C (5.29 g, 15.6 mmol), palladium(II) acetate (0.088 g, 0.39 mmol), triphenylphosphine (0.31 g, 1.2 mmol)and triethylamine (4.3 ml, 31 mmol). The reaction was stirred overnightat room temperature under a CO atmosphere. The mixture was thenpartitioned between water and ether and the organic layer was washedwith brine then dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was purified via silica gel chromatography(gradient elution, 0 to 30% diethyl ether-hexanes) to provide the titlecompound. MS (DCI/NH₃) m/e 247 (M+H)¹.

Example 9E(±)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

To a solution of 4-(trifluoromethyl)aniline (1.13 g, 7.00 mmol) indichloromethane (14 mL) at room temperature was added a 2N solution oftrimethylaluminum in toluene (3.50 mL, 7.00 mmol) in a dropwise fashion.The reaction was stirred for 30 minutes at room temperature under anitrogen atmosphere. A solution of Example 9D (862 mg, 3.50 mmol) indichloromethane (3 mL) was added and the mixture was stirred for 1 hourat room temperature under a nitrogen atmosphere. The reaction wasdiluted with ethyl acetate then quenched with 0.5N HCl. The organiclayer was separated and then washed successively with 1N NaOH, water,and brine. The organic layer was then dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified via silicagel chromatography (gradient elution with 0 to 15% ethyl acetate-[50%CH₂Cl₂:hexanes] to provide the title compound. MS (DCI/NH₃) m/e 460(M+H)¹.

Example 9F(3R)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared by chiral separation of Example 9E byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min to provide the first elutingenantiomer((3S)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide,retention time=10.3 min) along with the second eluting enantiomer((3R)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2/1-1,2′-bipyridine-4-carboxamide,retention time=12.2 min). ¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (br s, 1H),8.13 (dd, 1H, J=4.8, 1.7 Hz), 7.93 (d, 2H, J=8.5 Hz), 7.68 (d, 2H, J=8.5Hz), 7.55-7.52 (m, 1H), 6.95 (dd, 1H, J=7.1, 4.4 Hz), 6.70 (dd, 1H,J=3.0, 3.0 Hz), 3.87-3.81 (m, 2H), 3.15-3.11 (m, 2H), 3.03-2.93 (m, 1H),2.32 (s, 3H), 1.16 (d, 3H, J=6.8 Hz); MS (DCI/NH₃) m/e 376 (M+H)⁺; [α]²³_(D)−25.0° (c 0.40, CH₃OH).

Example 10(3R)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamideExample 10A 1-(3-(Trifluoromethyl)pyridin-2-yl)piperidin-4-one

The title compound was prepared using a similar procedure as describedin Example 9A, substituting 2-chloro-3-(trifluoromethyl)pyridine for2-chloro-3-methylpyridine. MS (DCI/NH₃) m/e 245 (M+H)⁺.

Example 10B(±)-3-Methyl-1-(3-(trifluoromethyl)pyridin-2-yl)piperidin-4-one

The title compound was prepared using a similar procedure as describedin Example 9B, substituting the product from Example 10A for the productfrom Example 9A. MS (DCI/NH₃) m/e 259 (M+H)⁺.

Example 10C(±)-3-Methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridin-4-yltrifluoromethanesulfonate

The title compound was prepared using a similar procedure as describedin Example 9C, substituting the product from Example 10B for the productfrom Example 9B. MS (DCI/NH₃) m/e 391 (M+H)⁺.

Example 10D (±)-methyl3-methyl-3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylate

The title compound was prepared using a similar procedure as describedin Example 9D, substituting the product from Example 10C for the productfrom Example 9C. MS (DCI/NH₃) m/e 301 (M+H)⁺.

Example 10E(±)-3-Methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared using a similar procedure as describedin Example 9E, substituting Example 10D for Example 9D. MS (DCI/NH₃) m/e430 (M+H)⁺.

Example 10F(3R)-3-Methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide

The title compound was prepared by chiral separation of Example 10E byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min to provide the first elutingenantiomer((3S)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide,retention time=12.8 min) along with the second eluting enantiomer((3R)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide,retention time=14.3 min). ¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (br s, 1H),8.58 (dd, 1H, J=4.8, 1.0 Hz), 8.12 (dd, 1H, J=8.1, 1.7 Hz), 7.92 (d, 2H,J=8.5 Hz), 7.67 (d, 2H, J=8.8 Hz), 7.25 (dd, 1H, J=7.8, 4.8 Hz), 6.65(dd, 1H, J=3.1, 3.1 Hz), 4.02-3.83 (m, 2H), 3.37 (dd, 1H, J=12.5, 4.4Hz), 3.17 (dd, 1H, J=12.5, 4.8 Hz), 3.05-2.94 (m, 1H), 1.06 (d, 3H,J=7.1 Hz); MS (DCI/NH₃) m/e 430 (M+H)⁺; [α]²³ _(D)−20.0° (c 0.40,CH₃OH).

Example 11(3S)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamideExample 11A(±)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared using a similar procedure as describedin Example 9E, substituting 4-[(trifluoromethyl)sulfonyl]aniline for4-(trifluoromethyl)aniline, and substituting Example 10D for Example 9D.MS (DCI/NH₃) m/e 494 (M+H)⁺.

Example 11B(3S)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared by chiral separation of Example 11A byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min to provide the first elutingenantiomer(3S)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide,retention time=14.9 min). ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H),8.59 (dd, J=5.5, 1.8 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.12 (dd, J=8.1,1.7 Hz, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.26 (dd, J=7.5, 4.6 Hz, 1H), 6.74(t, J=3.2 Hz, 1H), 4.03-3.84 (m, 2H), 3.37 (dd, J=12.6, 4.4 Hz, 1H),3.17 (dd, J=12.4, 4.9 Hz, 1H), 3.02-2.96 (m, 1H), 1.07 (d, 3H); MS(DCI/NH₃) m/e 494 (M+H)⁺; [α]_(D) ²⁰=+28° (c 1.0, CH₃OH).

Example 12(3R)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated as the second eluting enantiomer(retention time=17.3 min) from the chiral separation of Example 11A byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ10.63 (s, 1H), 8.59 (dd, J=5.5, 1.8 Hz, 1H), 8.14 (d, J=8.4 Hz, 2H),8.12 (dd, J=8.1, 1.7 Hz, 1H), 8.08 (d, J=8.4 Hz, 2H), 7.26 (dd, J=7.5,4.6 Hz, 1H), 6.74 (t, J=3.2 Hz, 1H), 4.03-3.84 (m, 2H), 3.37 (dd,J=12.6, 4.4 Hz, 1H), 3.17 (dd, J=12.4, 4.9 Hz, 1H), 3.02-2.96 (m, 1H),1.07 (d, 3H); MS (DCI/NH₃) m/e 494 (M+H)⁺; [α]_(D) ²⁰=−20° (c 1.0,CH₃OH).

Example 13(3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide Example 13A(±)-N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared using a similar procedure as describedin Example 9E, substituting 2-(4-aminophenyl)-2-methylpropanenitrile for4-(trifluoromethyl)aniline, and substituting Example 10D for Example 9D.MS (DCI/NH₃) m/e 429 (M+H)⁺.

Example 13B (3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated from the chiral separation of Example13A by HPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min as the first eluting enantiomerwith retention time=18.2 min) ¹H NMR (300 MHz, DMSO-d₆) δ 9.97 (s, 1H),8.57 (dd, J=5.5, 1.8 Hz, 1H), 8.11 (dd, J=8.1, 1.7 Hz, 1H), 7.74 (d,J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.24 (dd, J=7.4, 4.4 Hz, 1H),6.59 (t, J=2.9 Hz, 1H), 3.99-3.82 (m, 2H), 3.37 (dd, 1H), 3.16 (dd, 1H),3.02-2.96 (m, 1H), 1.67 (s, 6H), 1.05 (d, 3H); MS (DCI/NH₃) m/e 429(M+H)⁺.

Example 14(3R)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated from the chiral separation of Example13A by HPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min as the second elutingenantiomer (retention time=21.0 min) ¹H NMR (300 MHz, DMSO-d₆) δ 9.97(s, 1H), 8.57 (dd, J=5.5, 1.8 Hz, 1H), 8.11 (dd, J=8.1, 1.7 Hz, 1H),7.74 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.24 (dd, J=7.4, 4.4 Hz,1H), 6.59 (t, J=2.9 Hz, 1H), 3.99-3.82 (m, 2H), 3.37 (dd, 1H), 3.16 (dd,1H), 3.02-2.96 (m, 1H), 1.67 (s, 6H), 1.05 (d, 3H); MS (DCI/NH₃) m/e 429(M+H)³⁰; [α]_(D) ²⁰=−51° (c 0.3, CH₃OH).

Example 15(3S)—N-(4-tert-butylphenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamideExample 15A(±)-N-(4-tert-butylphenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared using a similar procedure as describedin Example 9E, substituting 4-tert-butylaniline for4-(trifluoromethyl)aniline. MS (DCI/NH₃) m/e 364 (M+H)⁺.

Example 15B(3S)—N-(4-tert-butylphenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated as the first eluting enantiomer(retention time=11.6 min) from the chiral separation of Example 15A byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ9.80 (s, 1H), 8.13 (dd, J=6.2, 1.7 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.53(dd, J=8.1, 1.8 Hz, 1H), 7.31 (d, J=8.3 Hz, 2H), 6.95 (dd, J=7.1, 4.0Hz, 1H), 6.60 (t, J=3.2 Hz, 1H), 3.83-3.79 (m, 2H), 3.12 (d, J=1.9 Hz,2H), 3.00-2.94 (m, 1H), 2.31 (s, 3H), 1.27 (s, 9H), 1.15 (d, 3H); MS(DCI/NH₃) m/e 364 (M+H)⁺; [α]_(D) ²⁰=+40° (c 1.0, CH₃OH).

Example 16(3R)—N-(4-tert-butylphenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated as the second eluting enantiomer(retention time=14.4 min) from the chiral separation of Example 15A byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ9.80 (s, 1H), 8.13 (dd, J=6.2, 1.7 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.53(dd, J=8.1, 1.8 Hz, 1H), 7.31 (d, J=8.3 Hz, 2H), 6.95 (dd, J=7.1, 4.0Hz, 1H), 6.60 (t, J=3.2 Hz, 1H), 3.83-3.79 (m, 2H), 3.12 (d, J=1.9 Hz,2H), 3.00-2.94 (m, 1H), 2.31 (s, 3H), 1.27 (s, 9H), 1.15 (d, 3H); MS(DCI/NH₃) m/e 364 (M+H)⁺; [α]_(D) ²⁰=−40° (c 1.0, CH₃OH).

Example 17(3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamideExample 17A(±)-N-(4-(2-cyanopran-2-yl)phenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared using a similar procedure as describedin Example 9E, substituting 2-(4-aminophenyl)-2-methylpropanenitrile for4-(trifluoromethyl)aniline. MS (DCI/NH₃) m/e 375 (M+H)⁺.

Example 17B(3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated as the first eluting enantiomer(retention time=16.1 min) from the chiral separation of Example 17A byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ9.96 (s, 1H), 8.13 (dd, J=6.2, 1.7 Hz, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.53(dd, J=8.2, 2.0 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 6.95 (dd, J=7.2, 3.9Hz, 1H), 6.64 (t, J=3.3 Hz, 1H), 3.85-3.81 (m, 2H), 3.12 (d, J=2.0 Hz,2H), 3.00-2.94 (m, 1H), 2.31 (s, 3H), 1.67 (s, 6H), 1.16 (d, 3H); MS(DCI/NH₃) m/e 375 (M+H)⁺; [α]_(D) ²⁰=+33° (c 1.0, CH₃OH).

Example 18(3R)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated as the second enantiomer (retentiontime=19.0 min) from the chiral separation of Example 17A by HPLC(Chiralcel OD column, elution with 20% (1:1 methanol:ethanol)-hexanes)at 0.7 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.13 (dd,J=6.2, 1.7 Hz, 1H), 7.74 (d, J=8.1 Hz, 2H), 7.53 (dd, J=8.2, 2.0 Hz,1H), 7.45 (d, J=8.1 Hz, 2H), 6.95 (dd, J=7.2, 3.9 Hz, 1H), 6.64 (t,J=3.3 Hz, 1H), 3.85-3.81 (m, 2H), 3.12 (d, J=2.0 Hz, 2H), 3.00-2.94 (m,1H), 2.31 (s, 3H), 1.67 (s, 6H), 1.16 (d, 3H); MS (DCI/NH₃) m/e 375(M+H)⁺; [α]_(D) ²⁰=−25° (c 0.3, CH₃OH).

Example 19(3S)-3-methyl-1-(3-methylpyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxamideExample 19A(±)-3-methyl-1-(3-methylpyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was prepared using a similar procedure as describedin Example 9E, substituting 6-(trifluoromethyl)pyridin-3-amine for4-(trifluoromethyl)aniline. MS (DCI/NH₃) m/e 377 (M+H)⁺.

Example 19B(3S)-3-methyl-1-(3-methylpyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated as the first eluting enantiomer(retention time=16.8 min) from the chiral separation of Example 19A byHPLC (Chiralcel OD column, elution with 20% (1:1methanol:ethanol)-hexanes) at 0.7 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ10.47 (s, 1H), 9.01 (d, J=3.3 Hz, 1H), 8.41 (dd, J=8.3, 2.9 Hz, 1H),8.14 (dd, J=4.9, 1.7 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.56-7.52 (m, 1H),6.96 (dd, J=8.5, 4.31H), 6.78 (t, J=3.4 Hz, 1H), 3.87-3.85 (m, 2H), 3.14(dd, J=7.9, 3.3 Hz, 2H), 3.02-2.94 (m, 1H), 2.32, (s, 3H), 1.18 (d,J=7.8 Hz, 3H); MS (DCI/NH₃) m/e 377 (M+H)⁺; [α]_(D) ²⁰=+20° (c 0.4,CH₃OH).

Example 20(3R)-3-methyl-1-(3-methylpyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide

The title compound was isolated as the second eluting isomer (retentiontime=18.4 min) from the chiral separation of Example 19A by HPLC(Chiralcel OD column, elution with 20% (1:1 methanol:ethanol)-hexanes)at 0.7 mL/min. ¹H NMR (300 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.01 (d, J=3.3Hz, 1H), 8.41 (dd, J=8.3, 2.9 Hz, 1H), 8.14 (dd, J=4.9, 1.7 Hz, 1H),7.87 (d, J=8.8 Hz, 1H), 7.56-7.52 (m, 1H), 6.96 (dd, J=8.5, 4.31H), 6.78(t, J=3.4 Hz, 1H), 3.87-3.85 (m, 2H), 3.14 (dd, J=7.9, 3.3 Hz, 2H),3.02-2.94 (m, 1H), 2.32, (s, 3H), 1.18 (d, J=7.8 Hz, 3H); MS (DCI/NH₃)m/e 377 (M+H)⁺; [α]_(D) ²⁰=−26° (c 0.4, CH₃OH).

e) BIOLOGICAL DATA In Vitro Data—Determination of Inhibition Potencies

Dulbecco's modified Eagle medium (D-MEM) (with 4.5 mg/mL glucose) andfetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan,Utah). Dulbecco's phosphate-buffered saline (D-PBS) (with 1 mg/mLglucose and 3.6 mg/l Na pyruvate, without phenol red), L-glutamine,hygromycin B, and Lipofectamine® were obtained from Life Technologies(Grand Island, N.Y.). G418 sulfate was obtained fromCalbiochem-Novabiochem Corp. (San Diego, Calif.). Capsaicin(8-methyl-N-vanillyl-6-nonenamide) was obtained from Sigma-Aldrich, Co.(St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human TRPV1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+ RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain 2000, 88,205-215). The resulting cDNA PCR products were subcloned into pCIneomammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hTRPV1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine®. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for TRPV1 receptor activity. Cellsexpressing recombinant homomeric TRPV1 receptors were maintained at 37°C. in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem)and 10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the TRPV1 receptor wasdetermined with a Ca²⁺ influx assay and measurement of intracellularCa^(2l) levels ([Ca^(2l)]_(i)). All compounds were tested over an11-point half-log concentration range. Compound solutions were preparedin D-PBS (4× final concentration), and diluted serially across 96-wellv-bottom tissue culture plates using a Biomek 2000 robotic automationworkstation (Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μMsolution of the TRPV1 agonist capsaicin was also prepared in D-PBS. Thefluorescent Ca²⁺ chelating dye Fluo-4 AM was used as an indicator of therelative levels of [Ca²⁺]_(i) in a 96-well format using a FluorescenceImaging Plate Reader (FLIPR)(Molecular Devices, Sunnyvale, Calif.).Cells were grown to confluency in 96-well black-walled tissue cultureplates. Then, prior to the assay, the cells were loaded with 100 μL perwell of Fluo-4 AM (2 μM, in D-PBS) for 1-2 hours at 23° C. Washing ofthe cells was performed to remove extracellular Fluo-4 AM (2×1 mL D-PBSper well), and afterward, the cells were placed in the reading chamberof the FLIPR instrument. 50 μL, of the compound solutions were added tothe cells at the 10 second time mark of the experimental run. Then,after a 3-minute time delay, 50 μL of the capsaicin solution was addedat the, 190 second time mark (0.05 μM final concentration)(finalvolume=200 μL) to challenge the TRPV1 receptor. Time length of theexperimental run was 240 seconds. Fluorescence readings were made at 1to 5 second intervals over the course of the experimental run. The peakincrease in relative fluorescence units (minus baseline) was calculatedfrom the 190 second time mark to the end of the experimental run, andexpressed as a percentage of the 0.05 μM capsaicin (control) response.Curve-fits of the data were solved using a four-parameter logistic Hillequation in GraphPad Prism® (GraphPad Software, Inc., San Diego,Calif.), and IC₅₀ values were calculated.

The compounds of the examples were tested in the assay described above.Representative (3S)-enantiomers of the present invention have IC₅₀ ofabout 20 nM to about 200 nM, and are more potent than theircorresponding (3R)-enantiomers, as shown in Table I.

TABLE I Example Stereoisomer hTRPV1 IC₅₀ (nM) 1 (S) 28 5 (R) 230 2 (S)20 7 (R) 84 3 (S) 20 6 (R) 760 4 (S) 26 10 (R) 480 8 (S) 63 9 (R) 380 11(S) 40 12 (R) 640 13 (S) 89 14 (R) 710 15 (S) 15 16 (R) 620 17 (S) 13 18(R) 1300 19 (S) 190 20 (R) 3100

The in vitro data demonstrates that (3S)-enantiomers of the presentinvention more effectively antagonize the TRPV1 receptor than thecorresponding (3R)-enantiomers. The unexpected improvement in theeffectiveness of the (3S)-enantiomers of the present invention makesthese compounds a better choice as therapeutic agents. This interestingproperty may result in better dosage quantities of the TRPV1 antagonistswith which the same beneficial therapeutic effects can be induced,either without or with diminished unwanted side effects. Compounds ofthe present invention include but are not limited to:

-   (3S)-3′-chloro-3-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;-   (3S)-3′-chloro-3-methyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;-   (3S)-3,3′-dimethyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;-   (3S)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;-   (3S)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;-   (3S)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide;-   (3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide;-   (3S)—N-(4-tert-butylphenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide;-   (3S)    —N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide;-   (3S)-3-methyl-1-(3-methylpyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide;    or a pharmaceutically acceptable salt thereof.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat pain as demonstrated byNolano, M. et al., Pain 1999, 81, 135-145; Caterina, M. J. and Julius,D., Annu. Rev. Neurosci., 2001, 24, 487-517; Caterina, M. J. et al.,Science, 2000, 288, 306-313; Caterina, M. J. et al., Nature, 1997, 389,816-824.

Physiological pain is an important protective mechanism designed to warnof danger from potentially injurious stimuli from the externalenvironment. The system operates through a specific set of primarysensory neurons and is activated by noxious stimuli via peripheraltransducing mechanisms (see Millan, Prog. Neurobiol., 1999, 57, 1-164for a review). These sensory fibers are known as nociceptors and arecharacteristically small-diameter axons with slow conduction velocities.Nociceptors encode the intensity, duration and quality of noxiousstimulus and by virtue of their topographically organized projection tothe spinal cord, the location of the stimulus. The nociceptors are foundon nociceptive nerve fibers of which there are two main types, A-deltafibers (myelinated) and C fibers (non-myelinated). The activitygenerated by nociceptor input is transferred, after complex processingin the dorsal horn, either directly, or via brain stem relay nuclei, tothe ventrobasal thalamus and then on to the cortex, where the sensationof pain is generated.

Pain may generally be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain are neuropathic pain (e.g. painful diabetic neuropathy,postherpetic neuralgia), carpal tunnel syndrome, back pain, headache,cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma,the characteristics of nociceptor activation are altered and there issensitization in the periphery, locally around the injury and centrallywhere the nociceptors terminate. These effects lead to a heightenedsensation of pain. In acute pain, these mechanisms can be useful inpromoting protective behaviors that may better enable repair processesto take place. The normal expectation would be that sensitivity returnsto normal once the injury has healed. However, in many chronic painstates, the hypersensitivity far outlasts the healing process and isoften due to nervous system injury. This injury often leads toabnormalities in sensory nerve fibers associated with maladaptation andaberrant activity (Woolf & Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivityfeature among the patient's symptoms. Patients tend to be quiteheterogeneous and may present with various pain symptoms. Such symptomsinclude: 1) spontaneous pain which may be dull, burning, or stabbing; 2)exaggerated pain responses to noxious stimuli (hyperalgesia); and 3)pain produced by normally innocuous stimuli (allodynia: Meyer et al.,Textbook of Pain, 13-44 (1994)). Although patients suffering fromvarious forms of acute and chronic pain may have similar symptoms, theunderlying mechanisms may be different and may, therefore, requiredifferent treatment strategies. Pain can also therefore be divided intoa number of different subtypes according to differing pathophysiology,including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli withthe potential to cause injury.

Pain afferents are activated by transduction of stimuli by nociceptorsat the site of injury and activate neurons in the spinal cord at thelevel of their termination. This is then relayed up the spinal tracts tothe brain where pain is perceived (Meyer et al., Textbook of Pain, 13-44(1994). The activation of nociceptors activates two types of afferentnerve fibers. Myelinated A-delta fibers transmit rapidly and areresponsible for sharp and stabbing pain sensations, whilst unmyelinatedC fibers transmit at a slower rate and convey a dull or aching pain.Moderate to severe acute nociceptive pain is a prominent feature of painfrom central nervous system trauma, strains/sprains, burns, myocardialinfarction and acute pancreatitis, post-operative pain (pain followingany type of surgical procedure), post-traumatic pain, renal colic,cancer pain and back pain. Cancer pain may be chronic pain such as tumorrelated pain (e.g. bone pain, headache, facial pain or visceral pain) orpain associated with cancer therapy (e.g. post-chemotherapy syndrome,chronic postsurgical pain syndrome or post radiation syndrome). Cancerpain may also occur in response to chemotherapy, immunotherapy, hormonaltherapy or radiotherapy. Back pain may be due to herniated or rupturedintervertebral discs or abnormalities of the lumber facet joints,sacroiliac joints, paraspinal muscles or the posterior longitudinalligament. Back pain may resolve naturally but in some patients, where itlasts over 12 weeks, it becomes a chronic condition, which can beparticularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by aprimary lesion or dysfunction in the nervous system. Nerve damage can becaused by trauma and disease and thus the term neuropathic pain'encompasses many disorders with diverse etiologies. These include, butare not limited to, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy,HIV neuropathy, phantom limb pain, carpal tunnel syndrome, centralpost-stroke pain and pain associated with chronic alcoholism,hypothyroidism, uremia, multiple sclerosis, spinal cord injury,Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic painis pathological, as it has no protective role. It is often present wellafter the original cause has dissipated, commonly lasting for years,significantly decreasing a patient's quality of life (Woolf and Mannion,Lancet, 1999, 353, 1959-1964). The symptoms of neuropathic pain aredifficult to treat, as they are often heterogeneous even betweenpatients with the same disease (Woolf & Decosterd, Pain Supp., 1999, 6,S141-S147; Woolf and Mannion, Lancet, 1999, 353, 1959-1964). Theyinclude spontaneous pain, which can be continuous, and paroxysmal orabnormal evoked pain, such as hyperalgesia (increased sensitivity to anoxious stimulus) and allodynia (sensitivity to a normally innocuousstimulus).

The inflammatory process is a complex series of biochemical and cellularevents, activated in response to tissue injury or the presence offoreign substances, which results in swelling and pain (Levine andTaiwo, Textbook of Pain, 45-56 (1994)). Arthritic pain is the mostcommon inflammatory pain.

Rheumatoid disease is one of the commonest chronic inflammatoryconditions in developed countries and rheumatoid arthritis is a commoncause of disability. The exact etiology of rheumatoid arthritis isunknown, but current hypotheses suggest that both genetic andmicrobiological factors may be important (Grennan & Jayson, Textbook ofPain, 397-407 (1994)). It has been estimated that almost 16 millionAmericans have symptomatic osteoarthritis (OA) or degenerative jointdisease, most of whom are over 60 years of age, and this is expected toincrease to 40 million as the age of the population increases, makingthis a public health problem of enormous magnitude (Houge & Mersfelder,Ann Pharmacother., 2002, 36, 679-686; McCarthy et al., Textbook of Pain,387-395 (1994)). Most patients with osteoarthritis seek medicalattention because of the associated pain. Arthritis has a significantimpact on psychosocial and physical function and is known to be theleading cause of disability in later life. Ankylosing spondylitis isalso a rheumatic disease that causes arthritis of the spine andsacroiliac joints. It varies from intermittent episodes of back painthat occur throughout life to a severe chronic disease that attacks thespine, peripheral joints and other body organs. Fernihough, J. et al.describe in Neuroscience Letters, 2005, 75-80 a potential role for TRPV1in the manifestation of pain behavior accompanied by osteoarthritischanges in the knee.

Compounds of the invention as TRPV1 antagonists are useful inameliorating acute and chronic inflammatory pain and postoperative painas demonstrated in Honore, P. et al., The Journal of Pharmacology andExperimental Therapeutics, 2005, 410-421.

Another type of inflammatory pain is visceral pain, which includes painassociated with inflammatory bowel disease (IBD). Visceral pain is painassociated with the viscera, which encompass the organs of the abdominalcavity. These organs include the sex organs, spleen and part of thedigestive system. Pain associated with the viscera can be divided intodigestive visceral pain and non-digestive visceral pain.

Commonly encountered gastrointestinal (GI) disorders that cause paininclude functional bowel disorder (FBD) and inflammatory bowel disease(IBD). These GI disorders include a wide range of disease states thatare currently only moderately controlled, including, with respect toFBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (TBS)and functional abdominal pain syndrome (FAPS), and, in respect of IBD,Crohn's disease, ileitis and ulcerative colitis, all of which regularlyproduce visceral pain. Elevated TRPV1 immunoreactivity has been observedin colonic sensory nerve fibers in patients with IBD (Szallasi, A., etal. Nature Reviews, 2007, 6, 357-373).

Other types of visceral pain include the pain associated withdysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple etiologies andthus can be classified in more than one area, e.g. back pain and cancerpain have both nociceptive and neuropathic components.

Other types of pain include: pain resulting from musculo-skeletaldisorders, including myalgia, fibromyalgia, spondylitis, sero-negative(non-rheumatoid) arthropathies, non-articular rheumatism,dystrophinopathy, glycogenolysis, polymyositis and pyomyositis; heartand vascular pain, including pain caused by angina, myocardicalinfarction, mitral stenosis, pericarditis, Raynaud's phenomenon,scleredoma and skeletal muscle ischemia; head pain, such as migraine(including migraine with aura and migraine without aura), clusterheadache, tension-type headache mixed headache and headache associatedwith vascular disorders; and orofacial pain, including dental pain, oticpain, burning mouth syndrome and temporomandibular myofascial pain. Ithas been shown that CGRP-receptor antagonists block the vasodilationeffects of CGRP and exhibits efficacy in patients with migraine andcluster headaches. CGRP is strongly co-expressed in many TRPV1expressing nerve fibers, it is plausible that activation of TRPV1 couldpartially underlie a neurogenic-mediated component of headache.

It is known that capsaicin, a TRPV1 agonist, induces cough and reducedairway conductance in human clinical trials. TRPV1 antagonists such ascapsazepine have been shown to block capsaicin and citric acid-inducedcough responses in guinea pigs as demonstrated by Geppetti, P. et al.,European Journal of Pharmacology, 2006, 533, 207-214. Thus, TRPV1antagonists demonstrate potential in the treatment of asthma, cough,chronic obstructive pulmonary disease (COPD) and bronchoconstriction asdemonstrated by Watanabe, N. et al., Pulmonary Pharmacology andTherapeutics, 2005, 18, 187-197 and Jia, Y. et al., British Journal ofPharmacology, 2002, 137, 831-836.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat bladder overactivityand/or urinary incontinence as demonstrated by Fowler, C. Urology 2002,55, 60-64.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat inflammatory thermalhyperalgesia as demonstrated by Davis, J. et al., Nature, 2000, 405,183-187.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used as for the treatment ofanxiety-related disorders as demonstrated by Marsch, R. et al., Journalof Neuroscience 2007, 27, 832-839.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used as for the treatment of disordersassociated with hyperdopaminergia such as psychosis, attention deficithyperactivity disorder and schizophrenia as demonstrated by Tzavara, E.et al., Biological Psychiatry 2006, 59, 508-515.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used as for the treatment of diabetesand obesity as demonstrated by Suni, A. and Sallazi, A., Trends inPharmacological Sciences 2008, 29, 29-36.

Compounds of the invention may be administered alone, or in combinationwith one or more other compounds of the invention, or in combination(i.e. co-administered) with one or more additional pharmaceuticalagents. For example, a compound of formula (I) or (II), or apharmaceutically acceptable salt or solvate thereof, may be administeredin combination with acetaminophen, or with one or more nonsteroidalanti-inflammatory drug (NSAID) such as, but not limited to, aspirin,diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac. In certainembodiments of the invention, the nonsteroidal anti-inflammatory drug (NSAID) is ibuprofen. Combination therapy includes administration of asingle pharmaceutical dosage formulation containing one or more of thecompounds of invention and one or more additional pharmaceutical agents,as well as administration of the compounds of the invention and eachadditional pharmaceutical agent, in its own separate pharmaceuticaldosage formulation. For example, a compound of formula (I) and one ormore additional pharmaceutical agents, may be administered to thepatient together, in a single oral dosage composition having a fixedratio of each active ingredient, such as a tablet or capsule; or eachagent may be administered in separate oral dosage formulations.

Where separate dosage formulations are used, compounds of the inventionand one or more additional pharmaceutical agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

When used in the above or other treatments, a therapeutically effectiveamount of one of the compounds of the invention can be employed in pureform or, where such forms exist, in pharmaceutically acceptable saltsthereof. Compounds of the invention can also be administered as apharmaceutical composition comprising the compounds of interest incombination with one or more pharmaceutically acceptable carriers. Thephrase “therapeutically effective amount” of the compound of theinvention means a sufficient amount of the compound to treat disorders,at a reasonable benefit/risk ratio applicable to any medical treatment.It will be understood, however, that the total daily usage of thecompounds and compositions of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well-known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the compound at levelslower than required to achieve the desired therapeutic effect and togradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered toa human or lower animal range from about 0.10 μg/kg body weight to about10 mg/kg body weight. More preferable doses can be in the range of fromabout 0.10 mg/kg body weight to about 1 mg/kg body weight. If desired,the effective daily dose can be divided into multiple doses for purposesof administration. Consequently, single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose.

f) PHARMACEUTICAL COMPOSITIONS

The invention also provides pharmaceutical compositions comprising ofcompounds of the invention, or pharmaceutically acceptable salts orsolvates thereof, formulated together with one or more pharmaceuticallyacceptable carriers. The pharmaceutical compositions can be formulatedfor oral administration in solid or liquid form, for parenteralinjection or for rectal administration.

The compounds identified by the methods described herein may beadministered as the sole pharmaceutical agent or in combination with oneor more other pharmaceutical agents where the combination causes nounacceptable adverse effects. For example, the compounds of thisinvention can be combined with an atypical antipsychotic. Specificexamples of suitable atypical antipsychotics include, but are notlimited to, clozapine, risperidone, olanzapine, quietapine, ziprasidone,zotepine, iloperidone, and the like. Thus, the present invention alsoincludes pharmaceutical compositions which are comprised oftherapeutically effective amount of compounds identified by the methodsdescribed herein, or pharmaceutically acceptable salts thereof, one ormore pharmaceutical agents as disclosed hereinabove, and one or morepharmaceutically acceptable carriers.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administration,including intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms can be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It also can bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug can depend upon its rateof dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, a parenterally administered drug formcan be administered by dissolving or suspending the drug in an oilvehicle.

Suspensions, in addition to the active compounds, can contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxidc, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation also can be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They can optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials useful for delaying release of the activeagent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, eardrops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, animal and vegetable fats, oils,waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention can also be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., p 33 et seq (1976).

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants. Ophthalmicformulations, eye ointments, powders and solutions are also contemplatedas being within the scope of this invention. Aqueous liquid compositionsof the invention also are particularly useful.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The term “pharmaceutically acceptable salts” as used herein,include salts and zwitterions of compounds of formula (I) which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response, and the like, are commensurate with areasonable benefit/risk ratio, and are effective for their intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by mixing together solutions of the compounds ofinvention and a suitable acid or base. The salt may precipitate from thesolution and be collected by filtration or may be recovered byevaporation of the solvent. The degree of ionization in the salt mayvary from completely ionized to almost non-ionized.

Suitable acid addition salts are formed from acids which form non-toxicsalts. Representative acid addition salts include, but are not limitedto acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, bicarbonate, butyrate, camphorate,camphorsulfonate, carbonate, citrate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, formate, fumarate, gluconate,glucuronate, glutamate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate, malate,malonate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,saccharate, stearate, succinate, sulfate, tartrate, thiocyanate,phosphate, hydrogenphosphate, dihydrogen phosphate, p-toluenesulfonate,trifluoroacetate, and undecanoate.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, zinc, and aluminum salts, and thelike, and nontoxic quaternary ammonia and amine cations includingammonium, tetramethylammonium, tetraethylammonium, methylamine,dimethylamine, trimethylamine, triethylamine, diethylamine, andethylamine. Other representative organic amines useful for the formationof base addition salts include ethylenediamine, ethanolamine,diethanolamine, piperidine, and piperazine.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention can be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987).

The invention also contemplates pharmaceutically acceptable compoundsthat when administered to a patient in need thereof may be convertedthrough in vivo biotransformation into compounds of the invention.

The compounds of the invention may exist in both unsolvated and solvatedforms. The term “solvate” is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm “hydrate” is employed when said solvent is water.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1. A compound of formula (I) essentially free of its (3R) enantiomer,

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or acombination thereof, wherein R¹ represents formula (i), (ii), (iii), or(iv)

R² represents formula (v), (vi), (vii), (viii), (ix), (x), (xi), or(xii)

R³ is C₁₋₆ alkyl; R⁴ represents optional substituents of R¹, and is, ateach occurrence, independently alkyl, alkenyl, alkynyl, —CN, halogen,—OR^(a), —NO₂, —N(R^(a))(R^(b)), —N(R^(b))C(O)R^(a),—N(R^(b))S(O)₂R^(a), —N(R^(b))C(O)OR^(a), —N(R^(b))C(O)N(R^(a))(R^(b)),—N(R^(b))S(O)₂N(R^(a))(R^(b)), —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))(R^(b)), —S(O)₂R^(a), —S(O)₂OR^(a), —S(O)₂N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—CN, haloalkyl, —(CR^(d)R^(e))_(q)—OR^(a),—(CR^(d)R^(e))_(q)—NO₂, —(CR^(d)R^(e))_(q)—N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)R^(a),—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂R^(a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)OR^(a),—(CR^(d)R^(e))_(q)—N(R^(b))C(O)N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—N(R^(b))S(O)₂N(R^(a))(R^(b)),—(CR^(d)R^(e))_(q)—C(O)R^(a), —(CR^(d)R^(e))_(q)—C(O)OR^(a),—(CR^(d)R^(e))_(q)—C(O)N(R^(a))(R^(b)), —(CR^(d)R^(e))_(q)—S(O)₂R^(a),—(CR^(d)R^(e))_(q)—S(O)₂OR^(a), or—(CR^(d)R^(e))_(q)—S(O)₂N(R^(a))(R^(b)); R⁵ and R⁶ are optionalsubstituents of R², and each of which at each occurrence isindependently alkyl, alkenyl, alkynyl, halogen, —CN, halogen, —OR^(a),—NO₂, —N(R^(a))(R^(b)), or haloalkyl; R^(a) and R^(b), at eachoccurrence, are each independently hydrogen, alkyl, or haloalkyl; R^(d)and R^(e), at each occurrence, are each independently hydrogen, alkyl,halogen, or haloalkyl; X¹ is O or S; m is 0, 1, 2, 3, 4, or 5; n is 0,1, 2, 3, or 4; p is 0, 1, or 2; q is 1, 2, 3, or 4; and s is 0 or
 1. 2.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R² represents formula (vi)


3. The compound of claim 2 or a pharmaceutically acceptable saltthereof, wherein R¹ is


4. The compound of claim 3 or a pharmaceutically acceptable saltthereof, wherein R³ is methyl.
 5. The compound of claim 2 or apharmaceutically acceptable salt thereof, wherein R¹ is


6. The compound of claim 5 or a pharmaceutically acceptable saltthereof, wherein R³ is methyl.
 7. The compound of claim 1 having formula(II)

or a pharmaceutically acceptable salt thereof, wherein R³, R⁴, and R⁵are as defined in claim
 1. 8. The compound of claim 7 or apharmaceutically acceptable salt thereof wherein R³ is methyl.
 9. Thecompound of claim 1 selected from the group consisting of(3S)-3′-chloro-3-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;(3S)-3′-chloro-3-methyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;(3S)-3,3′-dimethyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;(3S)-3-methyl-3′-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;(3S)-3,3′-dimethyl-N-[4-(trifluoromethyl)phenyl]-3,6-dihydro-2H-1,2′-bipyridine-4-carboxamide;(3S)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)-1,2,3,6-tetrahydropyridine-4-carboxamide;(3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-(trifluoromethyl)pyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide;(3S)—N-(4-tert-butylphenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide;(3S)—N-(4-(2-cyanopropan-2-yl)phenyl)-3-methyl-1-(3-methylpyridin-2-yl)-1,2,3,6-tetrahydropyridine-4-carboxamide;and(3S)-3-methyl-1-(3-methylpyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,6-tetrahydropyridine-4-carboxamideor a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound of formula (I) according to claim 1 ora pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable carriers.
 11. The pharmaceutical compositionaccording to claim 10 further comprising acetaminophen or one or morenonsteroidal anti-inflammatory drug, or a combination thereof.
 12. Amethod of treating pain, wherein pain comprises chronic pain,neuropathic pain, inflammatory pain, post herpetic neuralgia,neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy,nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns,back pain, visceral pain, cancer pain, dental pain, headache, migraine,carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, post strokepain, pelvic hypersensitivity, pelvic pain, menstrual pain, comprisingadministering a therapeutically effective amount of a compound offormula (I) according to claim 1, or a pharmaceutically acceptable saltthereof, to a subject in need thereof.
 13. The method according to claim12 further comprising the step of co-administering with acetaminophen orwith one or more nonsteroidal anti-inflammatory drug, or combinationthereof.
 14. The method according to claim 13 wherein the nonsteroidalanti-inflammatory drug is ibuprofen.
 15. A method of treatingincontinence, micturition disorder, renal colic, cystitis, stroke, acutecerebral ischemia, post stroke pain, cerebrovascular ischemia, multiplesclerosis, asthma, cough, chronic obstructive pulmonary disease (COPD),broncho-constriction, gastroesophageal reflux disease (GERD), dysphagia,ulcer, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD),colitis, Crohn's disease, cancer chemotherapy-induced emesis, orobesity, comprising administering a therapeutically effective amount ofa compound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.
 16. The methodaccording to claim 15 further comprising the step of co-administeringwith acetaminophen or with one or more nonsteroidal anti-inflammatorydrug, or a combination thereof.
 17. The method according to claim 16wherein the nonsteroidal anti-inflammatory drug is ibuprofen.
 18. Amethod of treating inflammatory states, comprising burns, rheumatoidarthritis and osteoarthritis comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.19. The method according to claim 18 further comprising the step ofco-administering with acetaminophen or with one or more nonsteroidalanti-inflammatory drug, or a combination thereof.
 20. The methodaccording to claim 19 wherein the nonsteroidal anti-inflammatory drug isibuprofen.